lower() vs casefold() and when to use, Details are given below.

Both .lower() and .casefold() act on the full range of Unicode codepoints

There’s some confusion in the existing answers, even the accepted one (EDIT: I was referring to this currently outdated version; the current one is fine). The distinction between .lower() and .casefold() has nothing to do with ASCII vs. Unicode, both act on the whole Unicode range of codepoints, just in slightly different ways. But both perform relatively complex mappings which they need to look up in the Unicode database, for instance:

>>> "Ť".lower()
'ť'

Both can involve single-to-multiple codepoint mappings, like we saw with "ß".casefold(). Look what happens to ß when you apply .lower()‘s counterpart .upper():

>>> "ß".upper()
'SS'

And the one example I found where .lower() also does this:

>>> list("İ".lower())
['i', '̇']

So the performance claims, like "lower() will require less memory or less time because there are no lookups, and it’s only dealing with 26 characters it has to transform", are simply not true.

The vast majority of the time, both operations yield the same thing, but there are a few cases (297 as of Unicode 13.0.0) where they don’t. You can identify them like this:

import sys
import unicodedata as ud

print("Unicode version:", ud.unidata_version, "n")
total = 0
for codepoint in map(chr, range(sys.maxunicode)):
    lower, casefold = codepoint.lower(), codepoint.casefold()
    if lower != casefold:
        total += 1
        for conversion, converted in zip(
            ("orig", "lower", "casefold"),
            (codepoint, lower, casefold)
        ):
            print(conversion, [ud.name(cp) for cp in converted], converted)
        print()
print("Total differences:", total)

When to use which

The Unicode standard covers lowercasing as part of Default Case Conversion in Section 3.13, and Default Case Folding is described right below that. The first paragraph says:

Case folding is related to case conversion. However, the main purpose of case folding is to contribute to caseless matching of strings, whereas the main purpose of case conversion is to put strings into a particular cased form.

My rule of thumb based on this:

• Want to display a lowercased version of a string to users? Use .lower().
• Want to do case-insensitive string comparison? Use .casefold().

(As a sidenote, I routinely break this rule of thumb and use .lower() across the board, just because it’s shorter to type, the output is overwhelmingly the same, and what differences there are don’t affect the languages I typically come across and work with. Don’t be like me though 😉 )

Just to hammer home that in terms of complexity, both operations are basically the same, they just use slightly different mappings — this is Unicode’s abstract definition of lowercasing:

R2 toLowercase(X): Map each character C in X to Lowercase_Mapping(C).

And this is its abstract definition of case folding:

R4 toCasefold(X): Map each character C in X to Case_Folding(C).

In Python’s official documentation

The Python docs are quite clear that this is what the respective methods do, they even point the user to the aforementioned Section 3.13.

They describe .lower() as converting cased characters to lowercase, where cased characters are "those with general category property being one of “Lu” (Letter, uppercase), “Ll” (Letter, lowercase), or “Lt” (Letter, titlecase)". Same with .upper() and uppercase.

With .casefold(), the docs explicitly state that it’s meant for "caseless matching", and that it’s "similar to lowercasing but more aggressive because it is intended to remove all case distinctions in a string".

print("∑∂˜∂ˆ´ˆˆçµµ∂˚ß˚ø≤∑∑π".casefold())     #∑∂˜∂ˆ´ˆˆçμμ∂˚ss˚ø≤∑∑π
print("∑∂˜∂ˆ´ˆˆçµµ∂˚ß˚ø≤∑∑π".lower())        #∑∂˜∂ˆ´ˆˆçµµ∂˚ß˚ø≤∑∑π

Was playing around and only casefold found the character ‘ß’. Might just stick with casefold if its more accurate even by the slightest.